1. Field of the Invention
This invention relates to a method for preparing a delivery system for an active ingredient by attaching the active ingredient to a linker through an acid-sensitive covalent bond, and attaching the linker to a portion of the subunits of a crosslinked polystyrene polymer. The invention also relates to a delivery system comprising an active ingredient covalently bonded through an acid-sensitive covalent bond to a linker, which is in turn covalently bonded to a portion of subunits of a crosslinked polystyrene polymer. The invention is further related to a method for treatment or prevention of gastric ulcers by administering a delivery system capable of delivering prostaglandin or prostacyclin drugs, especially misoprostol.
2. Related Background Art
Polymeric materials are frequently used to achieve controlled oral delivery of drugs. In most controlled-release devices, the drug molecule is not covalently bonded to the polymer, which acts merely as a barrier or as a reservoir from which the drug diffuses. The diffusion is often controlled by the degree of swelling of the polymer matrix on contact with aqueous media, as in the systems described in U.S. Pat. Nos. 5,275,824; 5,169,640; 4,921,707; 4,615,697; and in PCT Application WO 95/28916. However, some controlled-release systems are pH-selective, allowing release of the drug only within a specified pH range.
An example of pH-selective delivery can be found in polymeric systems consisting of interpenetrating networks of polyethylene glycol and polyacrylic acid. Such systems are disclosed in the International Journal of Pharmacy, Vol. 130, page 83 (1996) and in Archives of Pharmacal Research, Vol. 19, page 18 (1996). The polymeric network of these systems does not swell at gastric pH, but does swell on contact with the higher pH of the intestines, allowing release of the drug in the intestines. The swelling is believed to be due to deprotonation of the acrylic acid functional groups at the higher pH.
A delivery system to accomplish selective delivery to a particular site in the body is described in U.S. Pat. No. 4,663,308. In this system, a polymer which is crosslinked with a compound containing azo bonds is used as a coating for the drug substance. These azo bonds are reduced by enzymes in the large intestine, leading to cleavage of the crosslinks, causing the olymer coating to disintegrate, thereby releasing the rug in the large intestine.
Systems similar to the one described in U.S. Patent No. 4,663,308 are described in the Journal of Controlled Release: Vol. 19, page 121 (1992); and Vol. 36, page 109 (1995). The polymers employed in these systems do not swell at the typical gastric pH value of from 1 to 4, but pass unchanged into the intestine, where the higher pH value causes the polymer matrix to swell. The swelling allows enzymes in the intestine to enter the polymer and break the azo crosslinks in the polymer matrix, which in turn allows the drug to diffuse through the uncrosslinked polymer matrix.
None of the aforementioned controlled-release systems contains a drug which is covalently bonded to the polymer matrix. U.S. Pat. No. 4,228,152 describes a prostaglandin delivery system in which the prostaglandin molecule is covalently bonded to a polyacrylate or polymethacrylate chain directly, or indirectly through an oxyalkylenic, aminoalkylenic, or oxyaminoalkylenic chain. Release of the prostaglandin is effected by the gradual hydrolysis of the bonds connecting the prostaglandin to the polymer matrix. No suggestion is made either that the release is selective with regard to pH, or that the release is targeted to a particular site in the body.
A delivery system in which a covalently-bonded drug is selectively released at a predetermined pH is described in PCT Application No. WO 92/01477; U.S. Pat. No. 5,474,767; and Journal of Medicinal Chemistry, Vol. 36, p. 3087 (1993). In these references, pH-selective drug delivery systems comprise a drug covalently bonded to a linker by reaction with a silyl chloride functional group on the linker, thus forming an acid-sensitive silyl ether bond, and a polymer which is covalently bonded to the linker-drug combination. The polymer is crosslinked following bonding of the linker, or in some cases, prior to bonding of the linker. The exemplified preferred polymer in the inventions of WO 92/01477 and U.S. Pat. No. 5,474,767 is a polybutadiene containing amine functional groups. The invention of U.S. Pat. No. 5,474,767 is limited to polymers derived from non-aromatic unsaturated monomers. Other suitable polymers described in WO 92/01477 are polyamines, polybutadienes, copolymers of 1,3-dienes, polysaccharides, hydroxypropylmethylcellulose, amino-celluloses and proteins, e.g., chitosan, and polymers of acrylic and methacrylic acids, maleic copolymers thereof, and polymers having derivatizable olefinic bonds. While the pH-sensitive site-specific delivery systems of these references provide an excellent means of site specific drug delivery, polymeric pH-sensitive site-specific delivery systems having improved drug release performance characteristics would be highly advantageous.
This invention provides a method of preparing a polymeric delivery system for an active ingredient having enhanced site-specific release performance characteristics. The delivery system is formed either by attaching the active ingredient to a linker through an acid-sensitive covalent bond formed between a hydroxyl, CO2H, amino, mercapto, or enolizable carbonyl substituent on the active ingredient and a reactive group on the linker, and then attaching the linker to a portion of the subunits of a crosslinked polystyrene polymer through a linker-polymer covalent bond formed between the linker and a reactive group on the polymer, or by attaching a linker to the polymer and then attaching the active ingredient to the polymer-linker combination. The invention also provides a delivery system comprising an active ingredient covalently bonded through an acid-sensitive covalent bond to a linker which is in turn covalently bonded to a portion of subunits of a crosslinked polystyrene polymer. The invention further provides a method for treatment or prevention of gastric ulcers using a delivery system capable of delivering prostaglandin or prostacyclin drugs, especially misoprostol.